Methyl jasmonate binds to and detaches mitochondria-bound hexokinase
| Autor: | Tsafrir Bravman, Ariel G. Notcovich, Adrian Israelson, Z. Zaslavsky, Eliezer Flescher, Vered Bronner, Natalia Goldin, Laetitia Arzoine, Alina Heyfets, Varda Shoshan-Barmatz |
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| Rok vydání: | 2008 |
| Předmět: |
Cancer Research
Voltage-dependent anion channel Drug Evaluation Preclinical Cyclopentanes Biology Mitochondrion Acetates Transfection chemistry.chemical_compound Mice Adenosine Triphosphate Growth factor receptor Hexokinase Neoplasms Genetics Tumor Cells Cultured Animals Voltage-Dependent Anion Channels Glycolysis Oxylipins Molecular Biology chemistry.chemical_classification Membrane Potential Mitochondrial Mice Inbred BALB C Cell Death Dose-Response Relationship Drug Cell biology Mitochondria Rats Enzyme chemistry Biochemistry Apoptosis Cancer cell biology.protein Mitochondrial Swelling DNA Damage Protein Binding |
| Zdroj: | Oncogene. 27(34) |
| ISSN: | 1476-5594 |
| Popis: | Cellular bio-energetic metabolism and mitochondria are recognized as potential targets for anticancer agents, due to the numerous relevant peculiarities cancer cells exhibit. Jasmonates are anticancer agents that interact directly with mitochondria. The aim of this study was to identify mitochondrial molecular targets of jasmonates. We report that jasmonates bind to hexokinase and detach it from the mitochondria and its mitochondrial anchor—the voltage-dependent anion channel (VDAC), as judged by hexokinase immunochemical and activity determinations, surface plasmon resonance analysis and planar lipid bilayer VDAC-activity analysis. Furthermore, the susceptibility of cancer cells and mitochondria to jasmonates is dependent on the expression of hexokinase, evaluated using hexokinase-overexpressing transfectants and its mitochondrial association. Many types of cancer cells exhibit overexpression of the key glycolytic enzyme, hexokinase, and its excessive binding to mitochondria. These characteristics are considered to play a pivotal role in cancer cell growth rate and survival. Thus, our findings provide an explanation for the selective effects of jasmonates on cancer cells. Most importantly, this is the first demonstration of a cytotoxic mechanism based on direct interaction between an anticancer agent and hexokinase. The proposed mechanism can serve to guide development of a new selective approach for cancer therapy. |
| Databáze: | OpenAIRE |
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